The present invention relates to 6-alpha- and 6-beta-(aminomethyl and 1-aminoethyl)penicillanic acid 1,1-dioxides, pharmaceutically-acceptable salts thereof, conventional esters thereof which are hydrolyzable in vivo, bis-methanediol esters thereof; or mixed methanediol esters with said beta-lactamase inhibitors and sulbactam (penicillanic acid 1,1-dioxide), said methanediol esters also hydrolyzable in vivo. While some of these compounds possess antibacterial activity per se, their principal value is as beta-lactamase inhibitors. Thus they are useful in combination with conventional beta-lactam antibiotics (penicillins and cephalosporins) against microorganisms resistant or partially resistant to beta-lactam antibiotics through production of beta-lactamase enzymes. Also encompassed by the present invention are pharmaceutical compositions comprising a present beta-lactamase inhibiting compound and a known beta-lactam antibiotic; mixed bis-methanediol esters of the present beta-lactamase inhibiting compounds and either ampicillin or amoxicillin; pharmaceutical compositions of the latter mixed esters; methods of treating bacterial infections with either of the above pharmaceutical compositions; and compounds useful as intermediates in the preparation of these various compounds.
Related compounds, viz, penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo (Barth, U.S. Pat. No. 4,234,579); the bis-methanediol ester of sulbactam (Bigham, U.S. Pat. No. 4,309,347); various 6-beta-(hydroxymethyl)penicillanic acid 1,1-dioxides and esters thereof (Kellogg, U.S. Pat. No. 4,287,181); and 6-beta-(aminomethyl)penicillanic acid (McCombie, U.S. Pat. No. 4,237,051) have been previously described as beta-lactamase inhibitors useful in combination with beta-lactam antibiotics for the treatment of bacterial infections. Antibacterial bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide (Bigham, U.S. Pat. No. 4,244,951; Godtfredsen et al., U.S. Pat. No. 4,342,772) have also been described.
U.K. patent application No. 2,053,220, published Feb. 4, 1981, broadly discloses beta-lactamase inhibiting compounds of the formula ##STR1## The definitions of R.sub.a, R.sub.b and R.sub.c define literally an infinite number of compounds. These definitions, by appropriate selection of R.sub.a, R.sub.b and R.sub.c, may possibly define the simple 6-alpha and 6-beta-(aminoalkyl)penicillanic acid 1,1-dioxides of the present invention. No specific method for preparation of these compounds is present in the disclosure of this U.K. application, and there is no hint or suggestion that from among the infinity of compounds proposed, the present aminomethyl and 1-aminoethyl compounds are preferred compounds, possessing the particularly highly potent beta-lactamase inhibitory activity which we have determined for them.